Human natural killer (NK) cells are CD3(−)CD14(−)CD56(+) large granular lymphocytes that can kill infected or transformed cells that fail to express normal MHC class I molecules, thereby complementing protection provided by T cells. Similar to other lymphocytes, the total human NK cell population is heterogeneous, with the CD56bright and CD56dim subsets representing two phenotypically and functionally distinct subsets. CD56bright NK cells have few cytotoxic granules and low expression of the low affinity Fc receptor CD16 and killer immunoglobulin-like receptors (KIR), all consistent with poor cytolytic properties, but are capable of potent activation-induced cytokine and chemokine production.
By comparison, CD56dim NK cells have abundant cytolytic granules and high surface density expression of CD16 and KIR for potent antibody-dependent and natural cytolytic function, with little ability to produce immunomodulatory cytokines. Currently, the developmental relationship between the CD56bright and CD56dim human NK subsets is unclear, as is their site(s) of differentiation. While ≧90% of NK cells in peripheral blood are CD56dim, >90% of NK cells in lymph nodes are CD56bright. A recent study by Munz and colleagues showed that the resident CD56bright NK cells in lymph nodes and tonsils could be induced with interleukin (IL)-2 to adopt functional and phenotypic qualities of peripheral blood CD56dim NK cells, suggesting that CD56bright NK cells may be less mature than CD56dim NK cells in a sequential scheme of human NK development.
A correlate to this hypothesis is that the human NK cell precursor would need to reside in lymph nodes. Similar to other leukocyte populations, human NK cells are ultimately derived from CD34(+) hematopoietic precursor cells (HPC), yet the precise phenotype of the human NK precursor cell is unknown. Culture of purified human bone marrow CD34(+) hematopoietic precursor cells in either IL-2 or IL-15 primarily results in the generation of CD56bright NK cells. Similarly, mouse NK cells can be generated by in vitro culture of immature bone marrow progenitors in IL-2 or IL-15. Both IL-2 and IL-15 signal in part via a common IL-2/IL-15 receptor (R) β chain, and IL-2/IL-15Rβ-deficient mice are severely deficient in mature NK cells. Indeed, the lineage (Lin)(−)IL-2RP(+) population in mouse bone marrow has clearly been identified as the committed mouse NK precursor cell, however, IL-2/IL-15Rβ expression on freshly isolated human CD34(+) hematopoietic precursor cells is below the limits of detection by flow cytometry. Therefore, while the human NK precursor can be defined by its functional ability to differentiate into a CD56bright NK cell in response to IL-2 or IL-15, the precise phenotype of this CD34(+) hematopoietic precursor cell remains elusive.
Previous work by other laboratories has provided invaluable insight into the phenotype of the CD34(+) human NK precursor by associating surface antigen expression with NK precursor function. For example, Miller and colleagues provided early evidence that co-expression of CD7 on CD34(+) hematopoietic precursor cells selectively enriches for NK precursors. In addition, work by the Chen laboratory demonstrated that the co-expression of CD10 on bone marrow CD34(+) hematopoietic precursor cells identified the human common lymphoid progenitor (CLP) that included the NK precursor. Despite these advances, both CD34(+)CD7(−) and CD34(+)CD10(−) hematopoietic precursor cell populations also contain some NK precursors as determined by differentiation into CD56bright NK cells following incubation in IL-2 or IL-15. Thus, the “all-inclusive” human CD34(+) NK precursor cell remained to be identified.